Delving into the Latest Updates on LEI-401 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms-

Target

NAPE-PLD

Action

inhibitors

Mechanism

NAPE-PLD inhibitors(N-acyl phosphatidylethanolamine phospholipase D inhibitors)

Therapeutic Areas

NeoplasmsOther Diseases

Active Indication-

Inactive Indication

Neuroblastoma

Originator Organization

University of Leiden

Active Organization-

Inactive Organization

University of Leiden

License Organization-

Drug Highest PhasePendingPreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC24H31N5O2

InChIKeyGFHJYPQZBBHOCC-UXHICEINSA-N

CAS Registry2393840-15-6

Catalytic isomerization of alkenes is a powerful tool for the construction of complex synthetically valuable mols. due to their redox-neutral, atom- and step-economical nature.However, traditional catalytic asym. isomerization of alkenes typically required the use of a heteroat. group such as OH or NR₂ as the thermodn. driving force (i.e., the C=C double bond isomerizes along the direction of heteroat. groups).Here, we present a contra-thermodn. isomerization/asym. hydroboration of alkenyl alcs. and amines, in which the C=C double bond isomerizes along the opposite direction of OR and NR₂.Compared to the traditional thermal isomerizations, this reaction overcomes the unfavorable thermodn. bias to form a contra-thermodn. alkene intermediate, followed by an irreversible asym. terminal hydroboration to provide highly synthetically valuable chiral 1,n-boryl ethers and amines.This protocol shows a wide substrate scope, including allylic alcs., homoallylic alcs., alkenyl alcs., protected alkenyl alcs., and various free and protected alkenyl amines.The synthetic utilities and practicability of this method were demonstrated by gram-scale reactions, diverse product transformations, and its applications in the synthesis of bioactive mols.Preliminary mechanistic studies show that this reaction involves dissociative alkene isomerization and an asym. hydroboration of 1,1-disubstituted alkene intermediates.

01 Jan 2024·Psychopharmacology

Inhibition of fatty acid binding protein-5 in the basolateral amygdala induces anxiolytic effects and accelerates fear memory extinction

Article

Author: Ojima, Iwao ; Wang, Hehe ; Clement, Timothy ; Jones, Matthew J ; Laviolette, Steven R ; Uzuneser, Taygun C ; Rushlow, Walter J

RATIONALE:

The endocannabinoid (eCB) system critically controls anxiety and fear-related behaviours. Anandamide (AEA), a prominent eCB ligand, is a hydrophobic lipid that requires chaperone proteins such as Fatty Acid Binding Proteins (FABPs) for intracellular transport. Intracellular AEA transport is necessary for degradation, so blocking FABP activity increases AEA neurotransmission.

OBJECTIVE:

To investigate the effects of a novel FABP5 inhibitor (SBFI-103) in the basolateral amygdala (BLA) on anxiety and fear memory.

METHODS:

We infused SBFI-103 (0.5 μg-5 μg) to the BLA of adult male Sprague Dawley rats and ran various anxiety and fear memory behavioural assays, neurophysiological recordings, and localized molecular signaling analyses. We also co-infused SBFI-103 with the AEA inhibitor, LEI-401 (3 μg and 10 μg) to investigate the potential role of AEA in these phenomena.

RESULTS:

Acute intra-BLA administration of SBFI-103 produced strong anxiolytic effects across multiple behavioural tests. Furthermore, animals exhibited acute and long-term accelerated associative fear memory extinction following intra-BLA FABP5 inhibition. In addition, BLA FABP5 inhibition induced strong modulatory effects on putative PFC pyramidal neurons along with significantly increased gamma oscillation power. Finally, we observed local BLA changes in the phosphorylation activity of various anxiety- and fear memory-related molecular biomarkers in the PI3K/Akt and MAPK/Erk signaling pathways. At all three levels of analyses, we found the functional effects of SBFI-103 depend on availability of the AEA ligand.

CONCLUSIONS:

These findings demonstrate a novel intra-BLA FABP5 signaling mechanism regulating anxiety and fear memory behaviours, neuronal activity states, local anxiety-related molecular pathways, and functional AEA modulation.

01 Dec 2023·British Journal of Pharmacology

Disruption of tonic endocannabinoid signalling triggers cellular, behavioural and neuroendocrine responses consistent with a stress response

Article

Author: Hill, Matthew N ; Driever, Wouter P F ; Bains, Jaideep S ; Petrie, Gavin N ; van der Stelt, Mario ; Füzesi, Tamás ; Balsevich, Georgia ; Aukema, Robert J

Abstract:

Background and Purpose:

Endocannabinoid (eCB) signalling gates many aspects of the stress response, including the hypothalamic–pituitary–adrenal (HPA) axis. The HPA axis is controlled by corticotropin releasing hormone (CRH) producing neurons in the paraventricular nucleus of the hypothalamus (PVN). Disruption of eCB signalling increases drive to the HPA axis, but the mechanisms subserving this process are poorly understood.

Experimental Approach:

Using an array of cellular, endocrine and behavioural readouts associated with activation of CRH neurons in the PVN, we evaluated the contributions of tonic eCB signalling to the generation of a stress response.

Key Results:

The CB1 receptor antagonist/inverse agonist AM251, neutral antagonist NESS243 and NAPE PLD inhibitor LEI401 all uniformly increased Fos in the PVN, unmasked stress‐linked behaviours, such as grooming, and increased circulating CORT, recapitulating the effects of stress. Similar effects were also seen after direct administration of AM251 into the PVN, while optogenetic inhibition of PVN CRH neurons ameliorated stress‐like behavioural changes produced by disruption of eCB signalling.

Conclusions and Implications:

These data indicate that under resting conditions, constitutive eCB signalling restricts activation of the HPA axis through local regulation of CRH neurons in the PVN.

100 Deals associated with LEI-401

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